In the UK, leading researchers are preparing to submit an application for a large genetic study to two major funding agencies. The project is being led by Professor Chris Ponting of the University of Edinburgh, who is also vice chair of the CFS/ME Research Collaborative, and the UK ME/CFS Biobank at the London School of Hygiene & Tropical Medicine. I have a lot of respect for both Professor Ponting and Dr Luis Nacul, a clinical associate professor of epidemiology and public health at LSHTM and the co-principal investigator of CureME, the research unit at the university that hosts the biobank.
The funding application deadline is January 23rd. The ME/CFS Biomedical Partnership, a group developed to support the study, has posted an FAQ here and a form to demonstrate support for the study here. On his invaluable blog, ME/CFS Research Review, Simon McGrath recently wrote about the new project.
Here’s what he had to say in his post:
Researchers and patients are about to submit an application to the UK’s two big medical research funders for a 20,000-patient genetic study. The team want people with ME to sign up to show funders that the community backs the study and that large numbers of people are ready to join it.
Your action today could help the world’s largest ME/CFS genetics study win funding – and could make a huge difference for patients, helping to identify biological causes of the illness and unlocking far more UK funding for biomedical research.
On 23rd January, the ME/CFS Biomedical Partnership made up of researchers, people with ME/CFS and carers, will make a grant application to the Medical Research Council and the National Institute for Health Research. The Partnership needs £3.5 million for a very large genetic study into ME/CFS known as a genome-wide association study (GWAS).
The project will be led by Professor Chris Ponting at the University of Edinburgh in partnership with the UK ME/CFS Biobank at the London School of Hygiene & Tropical Medicine.
A GWAS aims to uncover some of the biological roots of disease. By scanning the whole of human biology and probing small DNA differences among people, a GWAS can help to pinpoint the genetic causes of disease and then can help to guide drug development. This method has helped to identify genes – and the molecular and cellular pathways associated with them – that play a role in diseases such as rheumatoid arthritis and Type II diabetes. (See my blog about the science of GWAS).
Drug development is now under way in numerous diseases because of GWAS. This, and the identification of biomarkers, could happen for ME/CFS too.
Because researchers are looking at small differences, they need to look at DNA data from a lot of people. The ME/CFS study will recruit around 20,000 patients whose DNA will be compared with that of similar numbers of people who do not have the disease. The DNA will be extracted from saliva samples, and the study uses a “spit and post” design, so even people who are bedbound or housebound can take part.
3 more reasons to back the project
1. Another big reason to support the study is that it includes creating a research cohort of 20,000 people – each clinically diagnosed with ME/CFS and who meet either the Canadian Consensus or Institute of Medicine (now called the National Academy of Medicine) criteria, both of which are widely used in biomedical research. The Partnership will set up a system to give other researchers easy access to DNA data, questionnaire answers and other information on this large number of people. This huge resource will help other researchers create robust studies more easily. The data will be made anonymous and held safely and securely.
2. All participants will be asked if they would be willing to be contacted in future about taking part in further studies. The hope is that the overwhelming majority of patients will say yes. Being able to easily recruit many patients will help researchers and should lead to better and faster research – and so more progress.
3. Patients are at the heart of this study. There is a Public Patient Involvement steering group with representation from patients and all the main charities. Two representatives, Sonya Chowdhury, CEO of Action for ME and a carer for someone with ME/CFS, and Andy Devereux-Cooke, a patient, are co-investigators on the study and sit on the management committee alongside two researchers.
Patients and charities have already started reaching out to other patients to sign up for the study, because the higher the number of sign-ups, the more the funding bodies will understand the need for the study and be reassured that patients will support it. Over 4,000 patients have already signed up in just two weeks over the holiday season. And we need more – could we make 10,000?
Speed is, of course, of the essence for patients. We’ve waited so long for good biomedical research, and for treatment. And the more patients who’ve said that they want to take part and want to be contacted if the work is funded, the faster the work can go. Signing up now should speed up the work later.
As Professor Chris Ponting says, “Patients with ME/CFS deserve the best that biomedical science has to offer, and it’s long overdue. But to get enough patients, fast enough, we’ll need a community-wide effort. Signing up early, and in large numbers, is the best way for patients to help us help them right now.”
Comments
20 responses to “The UK’s Proposed Genetics Study”
It’s about time we had a large genetic study so funding please – and I’d happily take part
I have 2 major concerns.
i) AFME is involved… massive red flag for me.
ii) the cohort is self selected and we already know that the numbers of people with a misdiagnosis of ME (or CFS ..whatever that is) is high.. between 40% and I think as much as 60%. Centres that use multiple hands-on/in person diagnostic tools (which of course involves searching for other known alternative diagnoses) including using the tightest criteria, ICC, find that many patients do not make the ‘cut’. Trying to co-opt 20,000 people with ME at arm’s length and then assessing them using questionnaires isn’t likely to provide a very clean cohort. Self selection plus subjective questionnaires… that ain’t a good start is it? Actually, imo, it’s the sort of ‘sloppy science’ for which we’ve been criticising the BPS school for many a day now.
I agree that “Patients with ME/CFS deserve the best that biomedical science has to offer, and it’s long overdue” but I’m not convinced that many scientists would regard this sort of cohort as representing the ‘best’ that can be offered.
Thus I’m conflicted. Part of me feels this is an utterly pointless waste of money which could be better spent, and part of me thinks it would wise to ensure my dna is included if only to skew a dirty database toward some meaningful data… BUT even I can’t be 100% sure of my diagnosis despite it coming from 4 different sources (none of which I really credit with understanding what ME really is) and having to rely on a very fragmented 50 year history of the disease where I’ve tried to rule out other diagnoses (mainly paid for privately) before coming to the conclusion that fitting both ICC and Ramsay criteria lends some weight to the diagnosis I’m lumbered with.
I wish I could be part of VanElzakker’s cohort simply to access the comprehensive testing that is part of the selection process so that I could be more sure of the diagnosis I have. VanElzakker’s is a team which takes the ‘scientific method’ seriously and properly screens to ensure (as well as medical science can presently manage) that the diagnosis of ME is the correct one.. I’m not sure that what’s on offer here can do that. I’d be interested to hear how the team think they can overcome the sullying that possibly one in every two people told they have ME (or CFS??) don’t have it?
Where tight cohorts have been used lately (and by that I mean ICC face to face screening etc) we’re seeing some really interesting results emerge. I’m guessing the tight cohort is the reason behind that… it makes sense. It’s a shame the good guys amongst the proposal above (and I do believe there are some ‘good guys’ in the mix) want to be involved with this clunky proposal. I can quite understand that mass dna data collection of people who really unarguably have ME might throw up some interesting data, but can a muddy cohort like this do that? I just can’t see it.
I hope that this study will be wholly focussed on biomedical research as the website suggests and won’t, at any time, lapse into anything related to the BPS approach, be that via researchers involved, the type of information gathered or the use of information gathered. Trust is easily lost but so hard to regain. ME sufferers must not be misled again.
“This method has helped to identify genes … that play a role in diseases such as rheumatoid arthritis and Type II diabetes”
If these are the best two examples of actual GWAS results, then mark me down as unimpressed and extremely skeptical of this approach. As far as I can understand, GWAS played no role in Professor Edwards’ development of an effective treatment for RA, and there is no effective treatment for Type II diabetes.
I started writing computer software for a living in 1974. I was forced to stop in 2007 due to this horrid disease. One thing I learned early on is that there is no magic in computers. And this sounds an awful lot like magic.
With AFME involved we already know the results will reflect cherry picked science. It’s time for everyone to recognize that poor science and poor participation selection will only extend the decades we have already suffered.
I’m sorry. I’m not impressed by this. We’ve been let down (shafted) too many times before
This will be worse than PACE. What happened to independent journalism?
“The ME/CFS study will recruit around 20,000 patients whose DNA will be compared with that of similar numbers of people who do not have the disease.”
Which disease? In order for good science we must reduce the variables. We know that ME and CFS are listed as two different conditions in the IOM report which went on to combine those two conditions under one umbrella (removing the most devastating symptoms that are unique to ME).
Patients across the globe KNOW that doctors are ill equipped to diagnose. Even the best of our doctors have been known to miss other conditions or diseases for far too many patients.
We need to get our ducks in a row before wasting money on research that can’t be realistically reliable. It is time we made sure anyone in an “ME” study was thoroughly screened for other diseases. We need diagnosis using the ICC followed up by ruling out other diseases for a common sense approach to getting the science right.
I am not aware that normal data bank systems have any system in place to remove data that no longer applies to the study. So it’s imperative that we get the right dataset to start with.
I am as concerned as everyone else that we get good quality biomedical research for ME/CFS. The scientists involved in this GWAS study understand the importance of accurate diagnosis. Diagnosis will, as I understand it, be based on both IOM and CCC criteria, using the questionnaires used by the UK ME/CFS biobank with PEM as a mandatory symptom. It is a genetic study, not a psychosocial study, and will be carried out by experts in these sorts of GWAS studies.
I do understand some people’s anxiety about Action for ME’s involvement, given their track record, but I think those concerns are misplaced in this instance. I was against the previous CMRC plans for the genetic study called MEGA which would have been led by Esther Crawley because I was afraid she would misuse questionnaire data for psychosocial studies and use too wide a definition of ME.
I don’t have those worries with this study. I trust the scientists involved and am satisfied they will do the best they can to get a cohort of patients who have ME/CFS. I am very pleased this study is planned and fully support it.
If they only want people from the UK (likely?) or will be recruiting world- or Europe-wide – it should say so.
I think this is a very worthwhile project. We have never had such a study before and it could help explain what causes the illness and help us identify subgroups.
To respond to concerns that this will leave out patients with ME as defined by the ICC: it will not, or at least there is no good reason in my eyes to think that it will. I understand that with 20000 participants the statistical power should be more than enough to overcome misdignoses and existence of subgroups in the data.
Just to mention to Jimells, genetic information on MHC Class II that came from what was equivalent of GWAS in the 1970s was absolutely essential to my work on rheumatoid arthritis. Further GWAS work in the 1990s also helped. RA is an excellent example. The genetic work laid the foundation for any meaningful theory of aetiology.
I see that supportive comments have been made subsequent to an appeal for them on S4ME forum. Everyone is entitled to their opinion on this, but I am still unable to fathom how questionnaires can properly ‘un-muddy’ a dirty cohort. At the very least it would seem eminently possible to include the quick-response questionnaire ‘Do I fit the International Consensus Criteria?’ (here: https://d3n8a8pro7vhmx.cloudfront.net/meadvocacy/pages/22/attachments/original/1478717636/ICC_Questionnaire_Nov_2016.pdf?1478717636) and use pretty basic algorithms to sieve out data specifically associated with that cohort. For those who support this enterprise I think having that option would at least partly satisfy the ‘small clique..of extremists’ who can see the folly of this venture as presently described.
Professor Edwards, thank you for the explanation. I’m not qualified to have an opinion on whether or not this research will be useful. Many years of illness and abuse by the medical industry has taught me to have a very cynical view of the medical research field, so my initial reaction to pretty much all research is, “Is it research or just more marketing?”
Lady Shambles’ suggestion above to include the quick-response questionnaire ‘Do I fit the International Consensus Criteria?’ WITHIN the study that will be based on the CCC/IoM seems a very sensible proposal and one that I suspect could be implemented with minimal additional burden on patients and researchers. Why wouldn’t you do this? Why would you give up the opportunity of seeing how 20,000 patients compare using the ICC criteria too (within the study) when it appears to be such an easy thing to enact and when other researchers are using the ICC criteria in their work? This sounds like an excellent compromise solution that might satisfy all camps and make more people want to participate.
I do understand why people are reluctant to take part in this study. When funders are involved, there will always be a trust issue as to whether pressure is being brought to bear to use particular criteria or look at particular aspects. But there is also the time issue. Some patients are desperate NOW, and finding answers quickly is literally a matter of life or death to them, so if a study uses criteria that are too broad to ‘catch’ key markers then a lot of time will have been wasted that they can’t afford. Decades have already been wasted. This study needs to be spot on and the researchers must convince patients that it is. So I would appeal to them to seriously consider this proposal and sell it to their funders.
One of the things the study should do is highlight the fact, as someone wrote below, the high level of misdiagnosis rate. I have known treatable causes of fatigue and exercise intolerance, all completely ignored by doctors because, apart from the appalling failure to train GPs to recognise rare and even not so rare illnesses, resulting in misreferrals to wrong specialist (eg referrals to neurology for problems that are endocrine and vice versa). CFS as a diagnosis is being deliberately used as a money-saving way of not treating real conditions or carrying out tests or referrals, therefore muddying the waters of people who have true ME. It is quite absurd that thanks to such poor training and practice, a whole array of treatable conditions are being labelled symptoms of CFS, rather than recognised and treated in their own right. It’s about time this shoddy practice of slapping an ME diagnosis on anyone with 6 months exercise intolerance, is challenged and one way to do that is to point out the different genetic causes of exercise intolerance. It is fundamental that true ME is differentiated from other conditions. Gene testing should then be able to assist diagnosis of those conditions that have a genetic component in future, saving money on wrong tests and referrals.
Thanks for all the feedback. I will respond to as many comments as I can manage.
Trish, @ME/CFS News, Sally Richardson — thanks for your support for the study.
Responses in order:
AfME
The study is highly unusual in giving a major role to patients and charities, even at the planning stage of the project. There is a Public Patient Involvement steering group chaired by Sonya Chowdhury of AfME. It also includes Andy Devereux-Cooke, from the S4ME forum, Charles Shepherd of the ME Association and the Countess of Marr representing the Forward-ME group of charities. This includes ME Research UK and almost all the UK charities, as well as #MEAction. The study has involvement and support from a lots of charities and patients. That’s a very good thing in my view.
Diagnosis
Diagnostic accuracy is important and the researchers for the study to take it seriously. So as well as requiring that people have a clinical diagnosis, there is the extensive screening questionnaire, developed by the UK ME/CFS Biobank. This questionnaire has been used to screen every patient in its biobank.
The study uses IOM and Canadian consensus criteria, and both have post-exertional malaise as a cardinal symptom. This is pretty unusual as a symptom, possibly unique. So applying PEM and all the other criteria to a clinical diagnosis is going to improve the diagnostic accuracy considerably.
As Jonathan Edwards points out later, this will be a very large study and that helps. The researchers do not expect diagnosis to be perfect but a GWAS doesn’t require perfect diagnosis to give robust results. My understanding is that if, say, it has only 80% accurate diagnosis with 20% various other illnesses, the small proportions of each of the various other illnesses won’t generate a strong enough signal to produce misleading results. Researchers will also be particularly focused on findings that are unique to ME/CFS, so not shared with MS, anaemia, depression et cetera.
Criteria
I understand that some people feel very strongly about ICC.
Almost all biomedical research that I am aware of is actually done using CCC. It is used by the NIH collaboratives at Cornell and Columbia Universities and Jackson laboratories. It is also used by Ron Davis at Stanford and the OMF collaborative at Harvard. I’m assuming the new Canadian collaborative will also use CCC. And the most compelling published finding I am aware of is the nanoneedle, and all the patients in that were selected using CCC patients. Almost all the two-day maximal exercise tests were also conducted on CCC patients.
The acid test is: do any studies find biological differences between CCC and ICC patients? I’m not aware of any.
Proposal to also use ICC criteria
I can really see the point of this.
However, I have looked at the ICC self-diagnosis questionnaire. My concern is that it is actually pretty long, since, to be user-friendly, it needs a separate item/check box for each symptom. That makes for a long questionnaire (or a shorter one that’s hard to understand).
Many patients responding to the study Q&A stressed the need not to place an excessive burden on patients so that as many as possible, particularly the severely-affected, are able to take part. Adding additional questions to ensure diagnosis according to ICC, which was considered by the researchers, will exclude some patients because of the burden.
So I don’t think it is viable to include ICC diagnosis because would exclude too many severe patients. However, I will pass this request on to the researchers.
What will be possible, and I understand will happen, is analysing CCC patients separately from IOM-only patients. I think that could be an invaluable analysis and show if the broadest criteria (still focusing on PEM) identify a different kind of patient.
CT: “There is no treatment for type II diabetes” so you are not impressed. This new GWAS sets out to help identify at least some of the biological mechanisms that cause this illness. And that would be a huge breakthrough because we still don’t know what causes ME. It would, of course, require further work by other researchers to confirm/establish details of any mechanisms. That work will hopefully lead on to developing new treatments.
Interestingly, GWAS for type II diabetes produced an unexpected biological finding, showing a role for a zinc transporter protein in the disease. As a result of this, new drugs targeting this transporter protein are currently in development.
More detail about some of the gains to date from GWAS here: https://mecfsresearchreview.me/2019/06/26/researchers-propose-deep-trawl-of-dna-to-help-uncover-the-causes-of-me-cfs/#success
But I would stress that this is a relatively new field, only recently coming-of-age, and is likely to see a lot more findings in the coming years. And ME/CFS should be part of this.
Sounds like magic? Not a bit of it. This is a very sophisticated, big data approach. It requires laborious work and a lot of careful analysis. My blog on it is a useful primer, but it only scratches the surface and if you want to know more, try reading the papers I have linked to within the blog. https://mecfsresearchreview.me/2019/06/26/researchers-propose-deep-trawl-of-dna-to-help-uncover-the-causes-of-me-cfs/
UK-only recruitment?
If the study wins funding, when it launches it will aim to recruit all patients from the UK and will make this clear. However, if this proves too hard, Plan B is to recruit internationally.
Thanks for all the feedback. I will respond to as many comments as I can manage.
Trish, @ME/CFS News, Sally Richardson — thanks for your support for the study.
Responses in order:
AfME
The study is highly unusual in giving a major role to patients and charities, even at the planning stage of the project. There is a Public Patient Involvement steering group chaired by Sonya Chowdhury of AfME. It also includes Andy Devereux-Cooke, from the S4ME forum, Charles Shepherd of the ME Association and the Countess of Marr representing the Forward-ME group of charities. This includes ME Research and almost all the UK charities, as well as #MEAction. The study has involvement and support from a loss of charities and patients. That’s a very good thing in my view.
Diagnosis
Diagnostic accuracy is important and the researchers for the study to take it seriously. So as well as requiring that people have a clinical diagnosis, there is the extensive screening questionnaire, developed by the UK ME/CFS Biobank. This questionnaire has been used to screen every patient in their biobank.
The study uses IOM and Canadian consensus criteria, and both have post-exertional malaise as a cardinal symptom. This is pretty unusual as a symptom, possibly unique. So applying all these symptoms to a clinical diagnosis is going to preserve the diagnostic accuracy considerably.
As Jonathan Edwards points out later, this will be a very large study and that helps. The researchers do not expect diagnosis to be perfect but a GWAS doesn’t require perfect diagnosis to give robust results. If, say, it has only 80% accurate diagnosis with 20% various other illnesses, the small proportions of each of the various other illnesses won’t generate a strong enough signal to produce misleading results. Researchers will also be particularly focused on findings that are unique to ME/CFS, so not shared with MS, anaemia, depression et cetera.
Criteria
I understand that some people feel very strongly about ICC.
Almost all biomedical research that I am aware of is actually done using CCC. It is used by the NIH collaboratives at Cornell and Columbia Universities and Jackson laboratories. It is also used by Ron Davis at Stanford and the OMF collaborative at Harvard. I’m assuming the new Canadian collaborative will also use CCC. And the most compelling published finding I am aware of is the nanoneedle, and all the patients in that were selected using CCC patients. Almost all the two-day maximal exercise tests were also conducted on CCC patients.
And I’m not aware of any studies indicating a biological difference between CCC and ICC patients.
Proposal to also use ICC criteria
I can really see the point of this.
However, I have looked at the ICC self-diagnosis questionnaire. My concern is that it is actually pretty long, since, to be user-friendly, it needs a separate item/check box for each symptom. That makes for a long questionnaire (or a shorter one that’s hard to understand).
The issue, raised by many patients responding to the study Q&A, is the need not to place an excessive burden on patients so that is many as possible, particularly the severely-affected, are able to take part. Adding additional questions to ensure diagnosis according to ICC, which was considered by the researchers, will exclude some patients because of the burden.
So I don’t think it is viable to include ICC diagnosis because would exclude too many severe patients.
What will be possible, and I understand will happen, is analysing CCC patients separately from IOM-only patients. I think that could be an invaluable analysis and show if the broadest criteria (still focusing on PEM) identify a different kind of patient.
CT: “There is no treatment for type II diabetes” so you are not impressed. This new GWAS sets out to help identify at least some of the biological mechanisms that cause this illness. And that would be a huge breakthrough because we still don’t know what causes it. It would, of course, require further work by other researchers to confirm/establish details of any mechanisms. That work will hopefully lead to new therapies.
Interestingly, the GWAS for type II diabetes have thrown up an unexpected biological finding, showing a role for a zinc transporter protein in the disease. As a result of that, new drugs targeting this transporter protein are currently in development.
More detail about the gains to date from GWAS year LINK. But I would stress that this is a relatively new field, only recently coming-of-age, and is likely to see a lot more findings in the coming years. And ME/CFS should be part of this.
Sounds like magic? Not a bit of it. This is a very sophisticated, big data approach. It requires laborious work and a lot of careful analysis. My blog on it is a useful primer, but it only scratches the surface and if you want to know more, try reading the papers I have linked to within the blog.
UK-only recruitment?
If the study wins funding, when it launches it will aim to recruit all patients from the UK and will make this clear. However, if this proves too hard, Plan B is to recruit internationally.
Such good news that 7,500 people have already expressed interest in taking part in this project, even though there’s been no funding for publicity. Just shows what could be achieved if the grant is approved, thus making available all sorts of additional ways to reach out to patients. Let’s all send our good and thanks wishes to the team and hope it’s successful.
I’ve not read the study design, but it seems that there is some degree of confusion because the setting up of the database is being combined with the design of queries to be used on the data for the purpose of identifying geneotypes common to M.E. sufferers.
I was hoping that the sampling will be for the purpose of setting up a databank of 20,000 *full genomes* [I’d imagine that Prof Edward’s ‘MHC’ work only involved sequencing just those genes: not whole genomes.]. If this is the case, then the objective should be to include the maximum of symptom and sign data to go with each genome record, so that the database can be queried by scientists working in any biomedical or genealogical/epidemiological etc. field. The database is the tool: not the study! You have to build the best possible tool, before you start to see what it can do.
Increasingly big data search methods are beginning to make possible the querying of unimaginably large amounts of data, to answer questions that we could not have imagined even a few years ago. DNA queries can run not just over databases compiled by specific disease researchers, but across databases of totally unrelated species to identify traits right through the whole evolution of life on the planet! For example: much of our DNA is actually remnants of viruses that have been repurposed down through the eons, to end up doing useful things for us! (You’ll hear quite a bit about this if you listen to the ‘TWiEvo’ podcast–though I find it rather hard to follow!)
Thus, the important thing is to consider any new DNA database as a part of an entire genome library of life on Earth. The utility of such a database sinks or falls by the amount of phenotypical and biographical information that is included with each data point (genome). So the question of ‘what criteria identifies M.E.’ is a question for just one study’s query of the database. Any particular query *should not* be used to handicap the database itself by depriving it of phenotypic data that may prove to be vitally important for later studies.
To set out to create a huge 20,000 genome database without maximising the phenotypical data included with each patient/subject’s data point, is akin to scientific vandalism. There is rarely going to be the opportunity for feeding individual subject data into the database once it has been compiled, so, however inconvenient it may feel when providing our data to compile the database with, it is much more important to take the extra time and make a database that is as complete as we can possibly make it, than it is to try and ‘blinker’ it in advance by excluding ‘non-qualifying case definitions’. I cannot stress the importance of this enough: *the case definitions are each separate queries you can interrogate the data with: they are NOT to be used to make the database, or they will cripple it and could even make it useless for anything else.*
To do so is actually reversing the purpose of a database: by restricting the *collection* of data stage to any case definition, you are actually only composing a one off, one query, set of data. This is not a database! You have to do the database first: *then* the queries: not the other way around.
Database design is a science in itself, and requires very clear thinking, and a separation of the data from the queries. When you see a database table, it may look very similar, whether it is a table of one query, or a view of the base data records themselves, but, in the latter case, there may be hundreds of columns of extra data off screen to the right, that are not of immediate use to you, but may be vital for generations of researchers and patients yet to come.
So please: don’t let’s skimp on what data goes into this new DNA base. I am a long time sufferer with an M.E. diagnosis that predates the modern criteria, and have my own records of symptoms and signs specific to my case, that probably uniquely identify me as much as the DNA does: both sets of data need to be gathered and stored together. Then the data can be searched for *any* disease. The proper collection of the BIG data is much more important than arguing over the design of the first ‘study’–this particular M.E. query is just one small step…
An update on the progress of the application. This was submitted Weds 22nd Jan and was able to include the fact that, up to end of Tues 21st Jan, 8,325 people had signed up to indicate their support of the proposed study. We hope to receive a decision by the end of March.
We’d like to thank the patient community for such a great level of support and David Tuller for posting this article about the application.